The Mediterranean fruit fly (medfly), Ceratitas capitata (Wiedemann), is a serious agricultural pest worldwide. Found in tropical/sub-tropical areas and established in Hawaii, it is a frequent invader of Florida, Texas, and California. The establishment of medfly in these regions of the continental United States poses a serious threat to horticultural production and trade, and results in an increased use of pesticides. Outbreaks of medfly in most agriculturally important regions of the United States are regulated with quarantines that trigger massive eradication and detection procedures to minimize potential damage to commercially valuable host fruit (USDA, APHIS, Fruit Fly Exclusion and Detection Programs 2011, Exotic Fruit Fly Strategic Plan FY2011-2015).
Maintaining a medfly-free continental United States has relied heavily on monitoring with an extensive network of trapping systems that employ chemical attractants. Currently, traps for male medfly utilize a synthetic lure trimedlure (TML), which is a mixture of 16 regio- and stereoisomers of tert-butyl esters of 4 (and 5)-chloro-2-methylcyclohexane-1-carboxylate (Beroza, M., et al., J. Agric. Food Chem., 9: 361 (1961)). Although classified as a weak attractant, TML has been in use for over 50 years while the development of more potent attractants, such as α-copaene—a host volatile (Flath, R. A., et al., J. Chem. Ecol., 10: 2595 (1994)) and ceralure (ethyl esters of 4 (and 5)-iodo-2-methylcyclohexane-1-carboxylate) (Warthen, J. D., et al., J. Chem. Ecol., 24: 1305 (1998))—a TML analog, have not been adopted due to the high economic costs of their synthesis (Tan, K. H., et al., Pheromones, Male Lures, and Trapping of Tephritid Fruit Flies, Epsky, N. D., et al., History and Development of Food-Based Attractants, IN: Trapping and the Detection, Control, and Regulation of Tephritid Fruit Flies: Lures, Area-Wide Programs, and Trade Implications, Shelly, T., et al., Eds., Springer: Dordrecht, 2014, pp. 15-118). TML is typically dispensed as a “gummy” containing 2 grams of attractant formulated in a polymer matrix. Over 1 million “gummies” are produced and sold annually for use as attractants in detection traps.

Several analogs of TML have been reported, however much of the structure-activity-relationship (SAR) stems, curiously, from bioassays involving isomeric mixtures (DeMilo A. B., et al., J. Econ. Entomol., 87: 1494 (1994); McGovern, T. P., et al., J. Econ. Entomol., 81: 1052 (1988)). Ceralure (CER), the iodo analog of TML, emerged from these SAR efforts. Commercial CER is also as a mixture of 16 regio- and stereoisomers of 4 (and 5)-iodo-2-methylcyclohexane-1-carboxylate. The isomeric components of commercially prepared TML and CER have been separated, at considerable effort, and their relative attractiveness has been established in bioassays. The most potent isomer of commercially available preparations of TML and CER have been identified as TML-C and CER-B1, respectively. While there are no reports of a stereoselective synthesis of TML-C, considerable effort has been directed towards the synthesis of the more potent isomers of commercial CER due to the improved efficacy of CER relative to TML and CER-B1 relative to TML-C (Warthen, J. D., et al., J. Chem. Ecol., 20: 569 (1994); Jang, E., et al., J. Econ. Entomol., 103: 1586 (2010)). An enantioselective synthesis of CER-B1 (Khrimian, A., et al., Tetrahedron, 59: 5475 (2003)) and a regioselective synthesis that yields only two CER isomers, CER-B1 and CER-A (Avery, J. W., et al., Tetrahedron Letters, 35: 9337 (1994); Khrimian, A., et al., Proceedings of 6th International Fruit Fly Symposium Stellenbosch, South Africa 279 (2002)) has been reported. Unfortunately, further refinement in the preparation of CER or CER-B1 have not been forthcoming and existing procedures for the synthesis of enriched mixtures of CER-B1 are economically unfavorable and are not suitable for industrial production since they are inefficient, difficult to scale-up, require tedious purification steps, and use toxic and costly reagents. Indeed, to our knowledge, no efficient preparations of CER-B1 has been developed that justify the use of CER over the commercially available mixture of TML isomers. Moreover, CER is known to be unstable in formulations and the environment (DeMilo, A. B., Ceralure, IN: USDA-ARS Action Plan for Fruit Flies Research, Faust, R. M.; Coppedge, J. R. Eds., U.S. Department of Agriculture, Agricultural Research Service, 1992, pp. 11).
The isomeric composition of TML influences attractiveness, and in turn, the efficiency of monitoring programs. To ensure consistent efficacy, the USDA Animal and Plant Health Inspection Service (APHIS) requires a certificate of analysis that TML must contain a minimum of 38% of trans-C isomer, no more than 24% of B2-isomer, and no more than 10% of cis-TML (total of 4 isomers). The development of commercial TML as a mixture of 8 diastereomers has placed an undue burden on the synthetic process, quality control, and the ability to accurately study TML in the laboratory and field.
Novel diastereomically pure compounds useful as medfly attractants would therefor constitute an advantage over the state of the art (TML and/or CER) by simplifying synthetic preparation, eliminating mixtures that complicate quality control, and increasing environmental stability. Herein we report such compounds.